Devices and methods for slurry generation

ABSTRACT

The present invention involves the use of a small profile device for preparation and/or delivery of cold slurry into the human body. The cold slurry can be generated within the device itself or within a separate small chamber, both of which produce a cold slurry using a cooling source and an injectable fluid. The delivery device provides continued agitation to the fluid/slurry through rotation and/or vibration of blades within the device. The fluid/cold slurry is cooled/kept cool through the use of an external cooling device, such as a cooling sleeve, that at least partially surrounds the delivery device. The cooling sleeve can cool or maintain the temperature of the cold slurry through a number of mechanisms. The cold slurry can be delivered using a device in accordance with the present invention to any tissue inside the body, including subcutaneous fat, visceral fat, and brown fat.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. No. 62/416,484 filed on Nov. 2, 2016 theentire disclosure of which is incorporated herein by reference.

BACKGROUND

The demand for procedures to reduce fat, often referred to as bodycontouring procedures, is large and continues to rise, especially withthe increasing number of minimally and non-invasive therapies available.According to the American Society of Aesthetic Plastic Surgery (ASAPS),in 2014, consumers spent approximately $12 billion on aestheticprocedures, including invasive, minimally-invasive, and non-invasive fatreduction procedures.

Invasive fat reduction procedures on the market include liposuction,abdominoplasty (“tummy tuck”), gluteoplasty (buttock lifts),brachioplasty (arm lift), thighplasty (thigh lift), lower rhytidectomy(neck lift), and mentoplasty (chin tightening). Invasive therapies carryrisks associated with surgical procedures, some of which can be lifethreatening. These include infection, scarring, perforation of organsand vessels, and hemorrhage. Additionally, invasive therapies are oftenpainful and typically require a lengthy recovery period.

Minimally-invasive fat reduction procedures include laser-assistedliposuction, laser lipolysis (i.e., the breakdown of lipids), radiofrequency lipolysis, ultrasound lipolysis, and injection lipolysis (e.g.injection of deoxycholic acid; KYBELLA). These procedures may require asurgical incision and/or the delivery of chemicals into the body, whichcan carry risks to the patient, and are often painful and producenon-uniform results.

Noninvasive procedures currently on the market include the use of radiofrequency, lasers, and ultrasound as well as the application of coldtemperatures to the surface of the skin (e.g. COOLSCULPTING by ZeltiqAesthetics, Inc.). These therapies are often time consuming and painful,while delivering minimal results.

Recently, minimally and non-invasive procedures to delivery cold to fattissue have been developed, with a non-invasive therapy known asCoolSculpting, as noted above, currently on the market. These proceduresare based on the principle that fat cells (adipose tissue) are moresensitive to cold temperatures than the skin or other surroundingtissues, with the cold temperatures causing the fat cells to undergoapoptosis, a natural biological process through which fat cells areeliminated from the body.

Non-invasive delivery of cool temperatures to the skin can be painful,may produce unsatisfactory results, and is very time consuming, with theassociated apparatus needing to be held on a patient's skin for alengthy amount of time. In contrast, delivery of a cold liquid such as aslurry, to the fat cells subdermally (or deeper to visceral fat tissues)provide a safe, controlled means for effective and selective reductionof fat cells. Methods for preparing a cold slurry and for delivering acold liquid to fat tissue through a cannula are disclosed inInternational Application Publication No. WO/2016/033380 and U.S. PatentApplication Publication No. 2013/0190744, each of which is incorporatedherein in its entirety. However, there exists a need for a cold slurrypoint of care delivery device that is convenient, requires minimalmaintenance and square footage, and is the least minimally invasive tothe patient.

SUMMARY

The present invention provides for a convenient means for generating acold slurry using an apparatus that has minimal parts and does notrequire extensive setup, expensive maintenance, or refrigeratedtransportation/on-site storage. The apparatus and methods of the presentinvention also provide targeted delivery of a cold slurry to fat cellswithout requiring a surgical incision.

Generally, the present invention involves the use of a small profileapparatus for preparation and/or delivery of cold slurry to the humanbody. The cold slurry can be generated within the device itself orwithin a separate small chamber, both of which produce a cold slurry atthe point of care using a cooling source and an injectable fluid. Whenthe cold slurry is produced in a separate chamber, it can then be easilytransferred to the delivery device, which can be a syringe-type device.The delivery device is capable of providing continued agitation to thefluid/slurry at the point of care, such as through rotation of bladeswithin the device, use of vibration or both. The fluid/cold slurry iscooled/kept cool inside the delivery device through the use of a smallprofile external cooling device, such as a cooling sleeve, that at leastpartially surrounds the device to provide cooling at the point of care.The cooling sleeve can cool or maintain the temperature of the coldslurry through a number of mechanisms, such as the provision of arefrigerant, the triggering of an endothermic reaction, and thecompression of gas. The cold slurry can be delivered using an apparatusin accordance with the present invention to any fat tissue inside thebody, including subcutaneous, visceral, and brown fat. See, for example,FIGS. 1A and 1B for diagrams of subcutaneous fat locations, as well assubcutaneous and visceral fat locations within the abdominal area. Forexample, the cold slurry can be delivered to, for example but notlimited to, fat tissue around the flank (i.e. “love handles”), abdomen,thigh area, upper arm, submental area under the chin, sub orbital fatpockets, above the knees, and any other pockets of subcutaneous fat forwhich reduction of the fat would be desirable.

In certain embodiments, the invention provides an apparatus for theproduction and/or delivery of a cold slurry. The apparatus includes acylindrical member comprising a first end, a second end, and alongitudinal axis extending through the first and second ends. Theapparatus further includes an outer surface extending between the firstand second ends along the longitudinal axis, and an interior lumendefined by an interior wall of the cylindrical member. The interiorlumen is configured to receive and hold a cold slurry. The apparatusfurther includes a plunger that is at least partially disposed withinthe interior lumen and configured to move within the cylindrical memberin the direction of the longitudinal axis. The plunger includes a head,a plunging member, and a rod extending between the head and the plungingmember along the longitudinal axis of the cylindrical member. Theapparatus further includes at least one needle extending from the secondend of the cylindrical member and an agitation device coupled to theplunger. The agitation device is configured to agitate the cold slurrywithin the interior lumen of the cylindrical member.

The apparatus can further include a motor coupled to the plunger. Themotor can coupled to the rod between the head and the plunging member.The motor can be coupled to the head of the plunger.

The agitation device can include at least one rotation blade extendingfrom the plunging member towards the second end of the cylindricalmember. The agitation device is configured to agitate the cold slurryupon rotation of the plunger. The agitation device can include a wireextending from the plunging member towards the second end of thecylindrical member along the longitudinal axis. The agitation device canfurther include one or more tentacles extending out from the wire andtoward the interior wall of the cylindrical member. The agitation devicecan further include a motor coupled to the plunger and configured tovibrate the wire.

The outer surface of the cylindrical member can include a conductivematerial, such as copper.

The apparatus can further include a sheath surrounding the cylindricalmember. The sheath can include a conductive material, such as copper.

The apparatus can further include a cooling sleeve surrounding at leasta portion of the cylindrical member. The cooling sleeve is configured tocool or maintain a temperature of the cold slurry within the interiorlumen of the cylindrical member. The cooling sleeve and the cylindricalmember can be in a concentric arrangement with a space formed between aninner surface of the cooling sleeve and the outer surface of thecylindrical member.

The apparatus can further include at least one tubular member locatedwithin the space. The tubular member is disposed axially about andextending at least partially around a circumference of the outer surfaceof the cylindrical member. The tubular member is configured to contain acooling fluid. The tubular member can be in the shape of a coil.

The apparatus can further include a container surrounding at least aportion of the cooling sleeve and fluidically connected to the tubularmember at least one location. The container is configured to hold acooling fluid and supply the cooling fluid to the tubular member.

The cooling sleeve can further include a cap configured to engage withand rotate the plunger of the cylindrical member.

The apparatus can further include a cap around the first end of thecylindrical member. The cap is configured to seat with the coolingsleeve towards the first end of the cylindrical member. A seal isprovided between the cap and the cooling sleeve. A first chemical can beprovided within an interior space of the cap and a second chemical canbe provided within the space between the cylindrical member and thecooling sleeve. In this embodiment, the seal separates the firstchemical from the second chemical. An endothermic reaction occurs whenthe first chemical and the second chemical are mixed together. The firstchemical and second chemical can be selected from the group consistingof: water, ammonium chloride, potassium nitrate, sodium thiosulphate,ammonium nitrate, ammonium thiocyanate, and barium hydroxideoctahydrate.

In some embodiments, the space between the cylindrical member and thecooling sleeve can forms a chamber. A container surrounding at least aportion of the cooling sleeve is fluidically connected to the chamber.The container is configured to hold a cooling fluid and supply thecooling fluid to the chamber. At least one inlet located between thechamber and the container is configured to allow the cooling fluid toflow from the container and into the chamber. The at least one inlet canbe operably coupled to a release mechanism to control the flow of thecooling fluid through the inlet.

The apparatus can further include a conductive membrane provided betweenthe chamber and the outer surface of the cylindrical member. The outersurface of the cylindrical member can include a conductive material. Theconductive membrane and the conductive material can be configured tointeract with each other when the cylindrical member is received withinthe cooling sleeve.

In certain embodiments, the apparatus includes at least one chamberdisposed within the space between the inner surface of the coolingsleeve and the outer surface of the cylindrical member. The at least onechamber extends along a second axis parallel to the longitudinal axis ofthe cylindrical member and is configured to contain a fluid. Theapparatus further includes a pressurized gas source configured tocompress the fluid in the at least one chamber. The at least one chambercan include a second plunger configured to compress the fluid whenactivated by the pressurized gas source. At least a portion of a wall ofthe at least one chamber that faces the cylindrical member can include aconductive membrane.

The apparatus can include a chamber configured to removably couple andsupply the cold slurry to the interior lumen of the cylindrical member.The chamber can include a top end and a bottom end. The top end includesa first connector that mates with a second connector located at thesecond end of the cylindrical member. The first connector and the secondconnector are configured to allow the cold slurry to flow from thechamber and into the interior lumen when mated.

The chamber can be configured to produce the cold slurry using a coolingfluid that cools an injectable fluid. The chamber can include a firstcompartment located at the top end of the chamber and configured tocontain the injectable fluid, a second compartment located between thetop and bottom ends of the chamber, and a third compartment located atthe bottom end of the chamber and configured to contain the coolingfluid. The second compartment can be configured to contain salt waterfilled particles. The first compartment and the second compartment canbe separated from each other by a separation member. The separationmember can be a breakable seal configured to break, such that a contentof the second chamber mixes with the injectable fluid in the firstcompartment.

In some embodiments, the second compartment and the third compartmentare in fluidic communication with each other through one or more valves.The one or more valves are configured to release the cooling fluid inthe third compartment into the second compartment when the one or morevalves are opened.

In other embodiments, the invention provides an apparatus for theproduction of a cold slurry for delivery to a tissue within a patient'sbody. The apparatus includes a first compartment containing aninjectable fluid, a second compartment, and a third compartmentcontaining a cooling fluid, which is provided to cool the injectablefluid. The second compartment can include a plurality of particles,which in some embodiments; can be a plurality of salt water filledparticles. The first compartment and the second compartment can beseparated from each other by a separation member. The separation membercan be a breakable seal configured to break, such that a content of thesecond chamber mixes with the injectable fluid in the first compartment.The second compartment and the third compartment can be in fluidiccommunication with each other through one or more release mechanisms.The release mechanisms are configured to release the cooling fluid inthe third compartment into the second compartment when the releasemechanisms are triggered.

In certain embodiments, the present invention provides a method ofgenerating a cold slurry using a delivery device. The method includesproviding a fluid to an interior lumen of a cylindrical member of adelivery device, agitating the fluid within the interior lumen using anagitation device, and cooling the fluid within the interior lumen togenerate cold slurry using an external cooling device. The externalcooling device at least partially surrounds the cylindrical member ofthe delivery device. The agitating and cooling of the fluid can be done,concurrently. The external cooling device can be a cooling sleevesurrounding at least a portion of the cylindrical member of the deliverydevice. The agitation device can include one or more rotation bladescoupled to a plunger that is at least partially disposed within theinterior lumen of the cylindrical member of the delivery device. Theagitation device can include a vibration mechanism.

In some embodiments, the method further includes ejecting the coldslurry from the delivery device using a plunger that is at leastpartially disposed within the interior lumen of the cylindrical memberof the delivery device. The ejected cold slurry can be delivered to oneor more tissue types selected from the group consisting of: subcutaneousfat, visceral fat, and brown fat. The ejected cold slurry can bedelivered to tissue in one or more areas selected from the groupconsisting of: tissue around the flank, abdomen, thigh area, upper arm,submental area under the chin, sub orbital fat pockets, above the knees,and any other pockets of subcutaneous fat for which reduction of the fatwould be desirable.

In certain embodiments, the present invention provides a method ofgenerating a cold slurry using a slurry generation chamber. The methodincludes providing a slurry generation chamber comprising: a firstcompartment containing an injectable fluid, a second compartment, and athird compartment containing a cooling fluid. The method furtherincludes releasing the cooling fluid from the third compartment into thesecond compartment to cool the injectable fluid in the first compartmentand generate cold slurry. The second compartment can include a pluralityof particles configured to agitate the injectable fluid while the coldslurry is being generated. The method can further include releasingcontents of the second compartment into the first compartment subsequentto the release of the cooling fluid from the third compartment into thesecond compartment. The method can further include providing agitationto the slurry generation chamber, such as shaking the slurry generationchamber.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is a diagram of subcutaneous fat locations in the body.

FIG. 1B is a diagram of subcutaneous and visceral fat locations withinthe abdominal area.

FIG. 1C is a diagram of brown fat locations in the body.

FIG. 2 shows a side view of an exemplary cold slurry delivery device.

FIG. 3 shows a perspective view of a cold slurry delivery apparatus withan agitation device in accordance with an embodiment of the presentinvention, while FIGS. 3A and 3B depict the movement of cold slurrywithin the apparatus according to the embodiment of FIG. 3. FIG. 3Cshows a side view of a single array of needles of an example cold slurrydelivery device.

FIGS. 4A and 4B depict the different embodiments for placement of amotor that effects rotation.

FIG. 5 shows a perspective view of a cold slurry delivery apparatus withan agitation device in accordance with another embodiment of the presentinvention.

FIG. 6 depicts a cold slurry delivery apparatus having a conductivematerial on its outer surface and FIG. 6A depicts a cross section of thewall of the apparatus showing the conductive material embedded in wall.

FIG. 7 depicts a cross sectional perspective view of a cold slurrydelivery apparatus with a cooling sleeve according to an embodiment ofthe present invention.

FIG. 8 depicts a cross sectional perspective view of a cold slurrydelivery apparatus with a cooling sleeve according to another embodimentof the present invention.

FIG. 9 depicts a cross sectional exploded perspective view of a coldslurry delivery apparatus with a cooling sleeve according to anotherembodiment of the present invention and FIG. 9A depicts a top-down crosssectional view taken at line 9A.

FIG. 10 depicts a cross sectional perspective view of a cold slurrydelivery apparatus with a cooling sleeve according to another embodimentof the present invention.

FIGS. 11A and 11B depict the creation of negative pressure on the fluidcontained within the cold slurry delivery device through the use of theplunger.

FIG. 12 depicts a cross sectional perspective view of the slurrygeneration chamber in accordance with an embodiment of the invention andFIG. 12A shows a close up view of a solid salt water filled sphere ofFIG. 12.

FIG. 13 depicts the transfer of cold slurry from a cold slurrygeneration chamber to the cold slurry delivery apparatus in accordancewith an embodiment of the present invention and FIG. 13A depicts a closeup view of the male and female connectors of FIG. 13.

FIG. 14 depicts the delivery of cold slurry to subcutaneous tissue usingan apparatus according the present invention.

DETAILED DESCRIPTION

The present invention involves the use of a small profile apparatus forpreparation and delivery of cold slurry to the human body. The coldslurry can be generated in the delivery device itself or can begenerated in and transferred from a separate chamber. Both methods forgenerating the slurry include the use of an injectable fluid, a coolingsource, and some form of agitation. When a separate chamber is used, thecold slurry is produced by combining, for example a cooling source, suchas a refrigerant, an injectable fluid, and an optional solid salt watersource within the chamber. When the cold slurry delivery device is usedto generate the cold slurry, the slurry is produced by external coolingof an injectable fluid within the device. An example of an externalcooling device is a cooling sleeve that cools fluid within the device ormaintains the temperature of the cold slurry delivered to the device.The cooling sleeve can cool or maintain the temperature of the coldslurry through a number of mechanisms, such as the provision of arefrigerant, the triggering of an endothermic reaction, and thecompression of gas. Both the cold slurry delivery device and theseparate chamber are capable of providing continued agitation to thefluid/slurry, such as through rotation of blades within the device, useof vibration, or both. The fluid/slurry is cooled/kept cool inside thecold slurry device by the use of external cooling, such as a coolingsleeve that easily slips over the device and provides cooling. The coldslurry can be delivered using an apparatus in accordance with thepresent invention to any fat tissue inside the body, includingsubcutaneous, visceral, and brown fat. For example but not limited to,the cold slurry can be delivered to fat tissue in any of the areas shownin FIGS. 1A-C, such as around the flank (i.e. “love handles”), abdomen,thigh area, upper arm, and submental area under the chin, sub orbitalfat pockets, above the knees, and other areas as shown in the figures.In principle, the cold slurry can be delivered to any pockets ofsubcutaneous fat for which reduction of the fat would be desirable.

In one embodiment, cold slurry is generated within the cold slurrydelivery device. The slurry is generated by providing a fluid to thecold slurry delivery device and cooling the fluid within the devicewhile providing agitation. The fluid provided to the cold slurrydelivery device can be any sterile, biocompatible fluid that is capableof being cooled to provide a cold slurry. Alternatively, the cold slurrycan be provided to the delivery device after being produced in aseparate chamber. Preferably the temperature of the fluid is cooled toor below about 10° C., 7° C., 5° C., 4° C., 3° C., 2° C., 1° C., 0° C.,−1° C., −2° C., −3° C., −4° C., −5° C., −10° C., −15° C., −20° C., −30°C., −40° C., and −50° C. The cold slurry generated will have a pluralityof sterile ice particles and will be suitable for injecting into asubject. Exemplary slurry compositions, slurry temperatures, andcross-sectional dimensions of ice particles are provided inInternational Application Publication No. WO/2016/033380, which isincorporated herein in its entirety. It is to be understood that anadvantage of the cold slurry in accordance with the present invention isthat the composition of the cold slurry is suitable for delivery totissues within a patient's body and remain within the body (e.g. noremoval of the slurry is necessary after cooling has been effected).

In one embodiment, the fluid contains one or more freezing pointdepressants, which depress the freezing point of the fluid, interferewith bonding between water molecules to prevent agglomeration of iceparticles, alter the viscosity of the fluid or otherwise affect theperformance of the fluid. Exemplary freezing point depressants areprovided in International Application Publication No. WO/2016/033380,which is incorporated herein in its entirety, and include salts (e.g.sodium chloride), ions, Lactated Ringer's solution, sugars (e.g.,glucose, sorbitol, mannitol, hetastarch, sucrose, or a combinationthereof), biocompatible surfactants such as glycerol, other polyols,other sugar alcohols, and/or urea, and the like. In one aspect, thefreezing point depressant content of the fluid is between about 5% andabout 40%, between about 10% and about 30% or between about 12% andabout 22%. In a preferred embodiment, the fluid includes a biocompatiblesurfactant such as glycerol. Such ingredients are believed to cause iceparticles to shrink and become rounder. These ingredients can also serveas a cryo-protectant for non-lipid-rich cells.

In order to produce a cold slurry that selectively destructs lipid-richcells while avoiding acute unselective necrosis, the slurry ispreferably isotonic relative to the subject's cells, e.g., having anosmolarity of about 308 mOsm/L. An exemplary cold slurry compositionincludes normal saline and 20% glycerol. In non-selective, broaderdestructive slurries, colder temperatures and greater destructive powercan be achieved by increasing the solute concentration (e.g., to 20% w/vsaline) to form a hypertonic solution (i.e., a solution having anosmolarity greater than about 308 mOsm/L) that will also disrupt cellsthrough osmotic pressure. It is noted that the solute concentration willdecrease as the ice melts. It is also contemplated that the coldslurries can further include a therapeutic compound.

Furthermore, the cold slurries generated from the initial fluid can havevarying ice contents, as provided in International ApplicationPublication No. WO/2016/033380, which is incorporated herein byreference. For example but not limited to, the cold slurries can containbetween about 0.1% and about 75% ice by weight, between about 0.1% and1% ice by weight, between about 1% and 10% ice by weight, between about10% and about 20% ice by weight, between about 20% and about 30% ice byweight, between about 30% and about 40% ice by weight, between about 40%and about 50% ice by weight, between about 50% and about 60% ice byweight, between about 60% and about 70% ice by weight, and greater thanabout 50% ice by weight. (The proportions of ice by volume are slightlyhigher due to the densities of solid and liquid water.)

The sterile ice particles can have a largest cross-sectional dimensionthat is less than about 2 mm, about 1.75 mm, about 1.5 mm, about 1.25mm, about 1 mm, about 0.9 mm, about 0.8 mm, about 0.7 mm, about 0.6 mm,about 0.5 mm, about 0.4 mm, about 0.3 mm, about 0.2 mm or about 0.1 mm.

The fluid can contain additional excipients, such as those found inSougata Pramanick et al., “Excipient Selection In Parenteral FormulationDevelopment,” 45(3) Pharma Times 65-77 (2013) and InternationalApplication Publication No. WO/2016/033380, both of which areincorporated herein by reference. Exemplary excipients include bulkingagents, such as sucrose, lactose, trehalose, mannitol, sorbitol,glucose, raffinose, glycine, histidine, PVP (K40); buffering agents,such as sodium citrate, sodium phosphate, sodium hydroxide, trisbase-65, tris acetate, tris HCl-65; tonicity modifiers, such asdextrose; collapse temperature modifiers such as dextran, ficoll,gelatin, and hydroxyethyl starch; antimicrobial preservatives, such asbenzalkonium chloride, benzethonium chloride, benzyl alcohol,chlorobutanol, m-cresol, myristyl gamma-picolinium chloride, parabenmethyl, paraben propyl, phenol, 2-phenoxyethanol, phenyl mercuricnitrate, and thimerosal; chelating agents, such as calcium disodium EDTA(ethylenediaminetetra acetic acid), disodium EDTA, calcium versetamideNa, calteridol, and DTPA; antioxidant and reducing agents, such asacetone sodium bisulfate, argon, ascorbyl palmitate, ascorbate

(sodium/acid), bisulfite sodium, butylated hydroxyl anisole, butylatedhydroxyl toluene (BHT), cystein/cysteinateHCl, dithionite sodium,gentistic acid, gentistic acid ethanolamine, glutamate monosodium,glutathione, formaldehyde sulfoxylate sodium, metabisulfite potassium,metabisulfite sodium, methionine, monothioglycerol(thioglycerol),nitrogen, propyl gallate, sulfite sodium, tocopherol alpha, alphatocopherol hydrogen succinate, thioglycolate sodium, thiourea, andanhydrous stannous chloride; solvents and co-solvents, such as benzylbenzoate, oils, castor oil, cottonseed oil, N,N dimethylacetamide,ethanol, dehydrated ethanol, glycerin/glycerol, N-methyl-2-pyrrolidone,peanut oil, PEG, PEG 300, PEG 400, PEG 600, PEG 3350, PEG 4000,poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil,vegetable oil, oleic acid, polyoxyethylene castor, sodiumacetate-anhydrous, sodium carbonate-anhydrous, triethanolamine, anddeoxycholate; buffers and pH-adjusting agents, such as acetate, ammoniumsulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonicacid, benzoate sodium/acid, bicarbonate-sodium, boric acid/sodium,carbonate/sodium, carbon dioxide, citrate, diethanolamine, glucono deltalactone, glycine/glycine HCl, histidine/histidine HCl, hydrochloricacid, hydrobromic acid, lysine (L), maleic acid, meglumine,methanesulfonic acid, monoethanolamine, phosphate (acid, monobasicpotassium, dibasic potassium, monobasic sodium, dibasic sodium andtribasic sodium), sodium hydroxide, succinate sodium/disodium, sulfuricacid, tartarate sodium/acid, and tromethamine (Tris); stabilizers, suchas aminoethyl sulfonic acid, asepsis sodium bicarbonate, L-cysteine,dietholamine, diethylenetriaminepentacetic acid, ferric chloride,albumin, hydrolyzed gelatin, insitol, and D,L-methionine; surfactants,such as polyoxyethylene sorbitan monooleate (TWEEN® 80), Sorbitanmonooleate, polyoxyethylene sorbitan monolaurate (TWEEN® 20), lecithin,polyoxyethylene-polyoxypropylene copolymers (PLURONICS®),polyoxyethylene monolaurate, phosphatidylcholines, glyceryl fatty acidesters, urea; complexing/dispersing agents, such as cyclodextrins (e.g.,hydroxypropyl-B-cyclodextrin, sulfobutylether-Bcyclodextrin); andviscosity building agents, such as sodium carboxymethyl cellulose,acacia, gelatin, methyl cellulose, polyvinyl and pyrrolidone.

The device 100 for generation and/or delivery of slurry is generallyshown in FIG. 2. The delivery device 100 includes a cylindrical member110 having a first (proximal) end 112, a second (distal) end 114; alongitudinal axis Y extending through the first end 112 and the secondend 114; and an outer surface 116 extending between the first end 112and the second end 114 along the longitudinal axis Y. The deliverydevice 100 also includes an interior lumen 130 defined by the interiorwall of the cylindrical member 110. The interior lumen 130 receives andholds fluid to be cooled as well as the final cold slurry. Thecylindrical member 110 also includes a ledge 150, or “arms”, extendingaround the first end 112 out from the cylindrical member 110 along aplane that is orthogonal to the longitudinal axis Y. The ledge 150 alsohas an opening concentric with the interior lumen 130. The ledge 150helps facilitate handling and delivery of fluid/slurry from the deliverydevice 100 and can also help secure the delivery device 100 within acooling sleeve, the latter of which is described in more detail below.

In one embodiment, the delivery device 100 is a syringe-type device,such as a Type 91-3 syringe. The cylindrical member 110 can be made ofany type of biocompatible pharmacologically inert material suitable foruse in holding and supplying fluids to be provided within a human body.Exemplary materials for the cylindrical member 110 include plastic, suchas polyethylene or polypropylene, and glass. The delivery device 100 canbe any size that suitable to hold one or more aliquots or doses of coldslurry for delivery to the desired tissue. The volume capacity of thedelivery device 100 is typically between 1 ml and 60 ml, althoughcapacity outside of those volumes is also contemplated.

The delivery device 100 also includes a plunger 120 at least partiallydisposed within the interior lumen 130. The plunger 120 is configured tomove in and out of the cylindrical member 110 along the longitudinalaxis Y of delivery device 100 through the first end 112. The plunger 120includes, a head 122, a plunging member 124, and a rod 126. The rod 126extends between the head 122 and the plunging member 124 along thelongitudinal axis Y of the delivery device 100. The plunging member 124is disposed at a predetermined distance from the head 122. The deliverydevice 100 also includes at least one needle 140 extending from thesecond end 114. The needle 140 will typically have a thickness between 7gauge and 34 gauge and a length between ¼″ and 10″, such as about ¼″,½″, 1″, 2″, 3″, 4″, 5″, 6″, 7″, 8″, 9″ or 10″. In one embodiment, thecylindrical member 110 narrows or tapers to a small opening at thesecond end 114. The small opening is configured to receive the needle140. Preferably, the needle 140 is a hypodermic needle. Exemplary needlematerials include, but are not limited to, stainless steel and carbonsteel, with or without nickel plating.

In order for fluid to pass through the needle 140 without getting stuckor blocking flow of the cold slurry, the largest cross-section of theice particles must be smaller than the internal diameter of the needle140. For example, the largest cross section can be less than about 95%of the internal diameter, less than about 85% of the internal diameter,less than about 75% of the internal diameter, less than about 65% of theinternal diameter, less than about 55%, and preferably about 50% of theinternal diameter. Exemplary ice particle sizes for various internaldiameters are provided in the table below, as disclosed in U.S. PatentApplication Publication No. 2017/0274011, which is incorporated hereinin its entirety. It is to be understood that these particles sizes areonly meant to be exemplary and not for limitation.

Nominal Recommended Largest Needle Internal Cross-Section of GaugeDiameter Ice Particles  7 3.81 mm 1.905 mm  8 3.429 mm 1.7145 mm  92.997 mm 1.4985 mm 10 2.692 mm 1.346 mm 11 2.388 mm 1.194 mm 12 2.159 mm1.0795 mm 13 1.803 mm 0.9015 mm 14 1.6 mm 0.8 mm 15 1.372 mm 0.686 mm 161.194 mm 0.597 mm 17 1.067 mm 0.5335 mm 18 0.838 mm 0.419 mm 19 0.686 mm0.343 mm 20 0.603 mm 0.3015 mm 21 0.514 mm 0.257 mm 22 0.413 mm 0.2065mm  22s 0.152 mm 0.076 mm 23 0.337 mm 0.1685 mm 24 0.311 mm 0.1555 mm 250.26 mm 0.13 mm 26 0.26 mm 0.13 mm  26s 0.127 mm 0.0635 mm 27 0.21 mm0.105 mm 28 0.184 mm 0.092 mm 29 0.184 mm 0.092 mm 30 0.159 mm 0.0795 mm31 0.133 mm 0.0665 mm 32 0.108 mm 0.054 mm 33 0.108 mm 0.054 mm 340.0826 mm 0.0413 mm

Returning back to the cold slurry delivery device 100 of FIG. 2, theplunger 120, including the head 122 and the rod 126, can be any type ofbiocompatible, pharmacologically inert material suitable for coming incontact with fluids to be provided within a human body. Exemplarymaterials for the plunger 120 include plastic, such as polyethylene orpolypropylene, and glass. With respect to the plunging member 124, aportion of or the entire plunging member 124 can be a rubber material,such that a seal is formed between the sides of the plunging member 124and the interior wall of the cylindrical member 110. The rubber materialcan be any rubber suitable for coming in contact with fluids to beprovided to the human body, such as natural rubber latex or a syntheticrubber.

During generation of the cold slurry within the interior lumen 130, theplunger 130 remains substantially in a stationary position with theplunging member 124 being located toward the first (proximal) end 112 ofthe cylindrical member 110, with the fluid being held between theplunging member 124 and the second (distal) end 114. In some aspects,the plunger 120 can be moved up through the cylindrical member 110, suchthat the plunging member 124 moves toward the first end 112 of thedelivery device 100. Such movement creates a negative pressure on thefluid, which depresses the freezing point of the fluid.

Once the cold slurry has been generated and is ready for delivery totissue using the delivery device 100, the needle 140 is used to piercethe patient's skin. Once the needle 140 is through the skin andpositioned at or near the target tissue, the plunger 120 is forceddownward toward the second end 114 of the cylindrical member 110. Theforce of the plunging member on the cold slurry, in conjunction with theincrease in pressure of the cold slurry, forces the cold slurry throughthe cylindrical member 110 and out of the needle 140 into the tissue. Inone aspect, a filter is provided within the cold slurry delivery device100 at the second end 114 to help control the particle size of slurryice particles that are delivered using the device 100.

In one embodiment, more than one needle is provided at the second end114 of the delivery device 100, as shown in FIG. 3C. The more than oneneedles can be provided in single row array (as shown), multiple rowarray (not shown), circular pattern (not shown), or any other convenientarrangement.

To facilitate the formation of a cold slurry as the fluid is beingcooled and/or to keep the sterile ice particles from aggregating as thecold slurry is being formed, agitation is provided within thecylindrical member 110. In one embodiment, agitation is provided throughthe rotation of one or more blades 210 and an optional support member215 coupled to the plunger, as shown in FIG. 3. In one embodiment, theblades 210 are strips that allow fluid to flow between the blades 210and the support member 215. In one aspect, the one or more blades 210can crisscross each other to form a figure eight or similar patternalong the longitudinal axis. In another embodiment, the one or moreblades 210 are solid in structure and extend out from the support member215 toward the interior wall of the cylindrical member 110 in such amanner that fluid is not able to flow between the support member 215 andthe blades 210. The blades 210 can extend out from the support member215 along a plane wherein one dimension of the plane is defined by thelongitudinal axis Y of the cold slurry delivery device 100.Alternatively, the blades 210 can extend out from the support member 215along a plane that intersects the longitudinal axis at an angle. Theblades 210 can be made out of any material that is suitable for contactwith sterile compositions to be delivered to the human body, includingthose exemplary materials previously provided with respect to thecylindrical member 110, plunger 120, and needle 140.

In one embodiment, the rotation of the plunger 120 causes rotation ofthe blades 210, which in turn causes the fluid/slurry to flow inmultiple directions, as shown in FIGS. 3A and 3B. In one embodiment,rotation of the plunger 120 is done manually by turning the plunger head122 using one's hand or a crank. In another embodiment, rotation isaided with the use of a motor 220. The motor can be coupled to the coldslurry delivery device 100 in any number of positions. For example, inone embodiment, the motor 220 is coupled to the plunger 120 along therod 126, as shown in FIG. 4A, with the rod 126 acting as a gear. In oneaspect, the motor 220 is coupled to the rod 126 between the head 122 andthe plunging member 124. In another embodiment shown in FIG. 4B, themotor 220 is coupled to the plunger 120 through the plunger head 122,which acts as a gear. In another aspect, the blades 210 are collapsibleand/or flexible, such that when force is applied to the plunger 120 andthe plunging member 124 is moved towards the second end 114, the blades210 collapse allowing the plunger 120 to travel through the cylindricalmember 110 and force the cold slurry out of the cold slurry deliverydevice 100.

In another embodiment, as shown in FIG. 5, agitation is provided throughthe use of vibration. In this embodiment, a wire 410 extends from theplunging member 124 toward the second end 114 of the cylindrical member110, along the longitudinal axis Y of the cold slurry delivery device100. Vibration is provided to the wire 410 by a motor 420, such as abattery powered vibrational motor, coupled to the plunger 120. Whenvibration is provided to the wire 410, the wire 410 moves in a number ofdirections (as depicted in the figure by the arrows) to provideagitation to the fluid/slurry. In one aspect, one or more wire tentacles415 can be provided along the wire 410, which extend out from the wire410 and toward the inside wall of the cylindrical member 110. Thetentacles 415 provide additional vibration and motion. Similar to theother components provided within the cold slurry delivery device 100,the wire 410 and tentacles 415 can be made of any material that isbiocompatible and pharmacologically inert.

It is to be understood that any other means known in the art to agitatea fluid can be used to provide agitation during generation of the coldslurry.

In order to effectuate the transfer of heat away from the coldslurry/transfer of cold to the cold slurry, the cold slurry deliverydevice 100 can be provided with a conductive material. In oneembodiment, as shown in FIGS. 6 and 6A, a conductive material 510 isprovided to the outer surface 116 of the cold slurry delivery device100. The conductive material 510 can be provided to the outer surface116 through a sheath 520 that surrounds the outer surface 116 of thecylindrical member 110. In one aspect, the conductive material isprovided as an inlay on the outer surface of the sheath 520. The inlaycan be disposed about the sheath 520, such that the inlay does notextend the entire depth of the sheath wall, as shown in FIG. 6A.

Alternatively or additionally, the cylindrical member 110 itselfcomprises a conductive material 510. In one aspect, the conductivematerial 510 is provided throughout the walls of the cylindrical member110. In another aspect, the conductive material 510 is provided to theouter surface 116 of the cylindrical member 110 as an inlay. In yetanother aspect, the conductive material 510 is provided to thecylindrical member 110, such that the inlay is in contact with the fluidcontained within the interior lumen 130 of the cylindrical member 110.

The conductive material 510 can be any material capable of effectingheat transfer. Exemplary conductive materials include, but are notlimited to, silver, copper, gold, aluminum, brass, zinc, nickel, iron,tin, phosphor bronze, steel, and lead. In a preferred embodiment, theconductive material 510 comprises copper.

The conductive material 510 can be provided on about 5% to about 95% ofthe surface of the sheath 520 and/or the cylindrical member 110, such ason about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%,95%, 100% or another other percentage in-between. In one aspect, theconductive material 510 is provided as strips that wrap around thesheath 520 and/or the cylindrical member 110. However, it is to beunderstood that the conductive material can be disposed on thesheath/cylindrical member 110 in any manner.

In one embodiment according to the present invention shown in FIG. 7,the apparatus also includes a cooling sleeve 600 that surrounds thecylindrical member 110 and cools or maintains a temperature of the coldslurry within the interior lumen 130. The cooling sleeve 600 can providecooling through any number of mechanisms, such as through the use ofcirculating refrigerant, the use of an endothermic reaction, and the useof pressure.

The cooling sleeve 600 is concentric with the outer surface 116 of thecylindrical member 110 and is spaced apart from the outer surface 116,such that a space 612 is formed between the cooling sleeve 600 and thecylindrical member 110. In one embodiment, the cooling sleeve 600 isconfigured to provide an interior chamber 640 for receiving the coldslurry delivery device 100. In one aspect, the cooling sleeve 600 has abottom 604 that extends below the second end 114 of the cylindricalmember 110 and a top 602 that extends above the first end 112 of thecylindrical member 110 and the plunger head 122, such that the coolingsleeve 600 encompasses the cold slurry delivery device 100 in itsentirety, as shown in FIG. 7. A removable cap 614 is provided at the top602 of the cooling sleeve 600 to allow for insertion and subsequentenclosure of the cold slurry delivery device 100 within the coolingsleeve 600. Similar to the components of the cold slurry delivery device100, the cooling sleeve 600 can be made out of any material that isbiocompatible and pharmacologically inert. However, because the coolingsleeve 600 may not come in contact with the fluid contained within thecold slurry delivery device 100, additional materials can be used.

In one embodiment in which rotation is used to agitate the fluid withinthe cold slurry delivery device 100, a motor 620 and associated gear canbe disposed on/coupled to the device 100, such as on the plunger head122 or rod 126, as disclosed previously and as shown in FIG. 7. Themotor 620 and associated gear can also be disposed on/coupled to thecooling sleeve 100, such as on the cap 614 along the longitudinal axisor around the top edge of the cap 614, the edge is being provided withgear teeth, as also shown in FIG. 7. The motor 620 can also be disposedon/coupled to the cooling sleeve 600 at the second end 114 of thecylindrical member 110. It is also to be understood that the motor 620and associated gear can be disposed at any other location within or onthe cold slurry delivery device 100 or the cooling sleeve 600 thatfacilitates rotation and is not limited to the examples provided aboveand that the gear teeth can be located inside or outside one or both ofthe cooling sleeve 600 and the cold slurry delivery device 100.

In one embodiment in which cooling via the cooling sleeve 600 iseffected through the use of a circulating refrigerant, at least onetubular member 650 is provided within the space 612 between the coolingsleeve 600 and the cylindrical member 110, as shown in FIG. 7. Thetubular member 650 is disposed axially about the outer surface 116 ofthe cylindrical member 110, with the tubular member 650 extending atleast partially around a circumference of the outer surface 116. In apreferred embodiment, the tubular member 650 is wrapped around thecylindrical member 110 to form a coil. The tubular member 650 is hollowto allow for cooling fluid to flow through its interior.

In one aspect, a cooling fluid supply unit 630 is provided to thecooling sleeve 600 for supplying the cooling fluid to the cooling sleeve600. In one embodiment, the cooling fluid supply unit 630 surrounds atleast a portion of the cooling sleeve 630, including the bottom 604 ofthe cooling sleeve 600, as shown in FIG. 7. The cooling fluid supplyunit 630 is fluidically connected to the tubular member 650 in order tosupply cooling fluid to the tubular member 650. In one embodiment, thecooling fluid supply unit 630 is similar to a circuit chiller, whichprovides a stream of cooling fluid upon the depression of a trigger.

The cooling fluid can be any fluid capable of providing cooling. In oneembodiment, the cooling fluid is a commercially available refrigerant,such as Ammonia (R717), HCF (134a/R-134a), CO₂ (R-744), and HFO-1234yf(2,3,3,3-Tetrafluoropropene) or others, such as R404A, R407A, R744,R290, and R410A. In another embodiment, the cooling fluid is liquidnitrogen.

The cooling sleeve 600 can also provide cooling through the use of anendothermic reaction, as shown in FIG. 8. In this embodiment, a firstchemical 660 is provided within an interior space of the cap 614 of thecooling sleeve 600 and a second chemical 665 is provided within thespace 612 between the cooling sleeve 600 and the cylindrical member 110(not shown).

The first and second chemicals 660, 665 are chosen such that the mixtureof the two chemicals within the space 612 between the cooling sleeve 600and the outer surface 116 of the cylindrical member 110 produces anendothermic reaction, thus providing cooling to the cold slurry deliverydevice within a chamber 640. Exemplary combinations of chemicals thatproduce an endothermic reaction include, but are not limited to thefollowing: ammonium thiocyanate and barium hydroxide octahydrate; waterand sodium thiosulphate; water and ammonium chloride; water and ammoniumnitrate; and water and potassium nitrate.

A seal 618 is provided between the cap 614 and the remainder of thecooling sleeve 600 to prevent the first chemical 660 and the secondchemical 665 from mixing with each other until cooling is desired. Theseal 618 can be broken by any means known in the art, such as bytwisting the cap 614 to break the seal 618. Once the seal 618 is broken,the first chemical 660 is released from the cap 614 and enters the space612 and mixes with the second chemical 665 to provide an endothermicreaction.

The cooling sleeve 600 can also provide cooling through the use of acooling fluid that circulates through the space 612 between thecylindrical member 110 and the cooling sleeve 600, as shown in FIG. 9.In this embodiment, the space 612 forms a chamber for holding andcirculating a fluid, preferably a cooling fluid.

Similar to the embodiment featured in FIG. 7, the cooling fluid can beany fluid capable of providing cooling. In one embodiment, the coolingfluid is a commercially available refrigerant, such as Ammonia (R717),HCF (134a/R-134a), CO₂ (R-744), and HFO-1234yf(2,3,3,3-Tetrafluoropropene) or others, such as R404A, R407A, R744,R290, and R410A. In another embodiment, the cooling fluid is liquidnitrogen.

In one aspect, the cooling fluid is provided to the cooling sleeve 600via the cooling fluid supply unit 630 that surrounds at least a portionof the cooling sleeve 600. The cooling fluid can be released from thecontainer and into the space 612 through one or more inlets 670 (orvalves). The inlets 670 remain closed until triggered by a signal from arelease mechanism 680. Once triggered by the signal, the one or moreinlets 670 will open and allow passage of the cooling fluid from thecooling fluid supply unit 630 and into the space 612. Fluid flowsthrough the space 612 in a direction parallel to the longitudinal axis,as shown in FIG. 9, as well as in an circular direction, as shown in thetop-down cross-sectional view of FIG. 9A, which is taken at line 9A.

In another aspect, a conductive membrane 618 is provided between thespace 612 and the chamber 640, as shown in FIG. 9A, such that theconductive membrane 618 interacts with the conductive material 510provided on at least the outer surface of the cold slurry deliverydevice 100. Similar to the conductive material 510, the conductivemembrane 618 can be any material capable of effecting heat transfer.Exemplary conductive membrane materials include, but are not limited to,silver, copper, gold, aluminum, brass, zinc, nickel, iron, tin, phosphorbronze, steel, and lead. In a preferred embodiment, the conductivemembrane 618 comprises copper.

The cooling sleeve 600 can also provide cooling through the use ofpressure to lower the temperature, as shown in FIG. 10. In thisembodiment, at least one chamber 613 is disposed within the space 612.The at least one chamber 613 extends along a second axis parallel to thelongitudinal axis. In one aspect the chamber 613 is cylindrical inshape. The chamber 613 contains a fluid to be compressed. Any number ofchambers can be provided within the space 612, such as 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, and any number in between.

Pressurized gas for compressing the fluid in the one or more chambers613 is provided within the cap 614, with the cap 614 forming a highpressure gas chamber. In one aspect, a plunger 615 is provided withinthe chamber 613. When cooling is desired, the compressed gas is releasedfrom the cap 614 via gas release mechanism 690. The compressed gaspushes downward on the plunger 615, thus activating the plunger 615 tocompress the fluid. The rapid compression of fluid creates rapid coolingto the chamber 640, thus cooling and/or maintaining the cold temperatureof the fluid/slurry within the cold slurry delivery device 100 beingheld within the chamber 640.

In one aspect of this embodiment, at least a portion of a wall of thechamber 613 that faces the cylindrical member 110 comprises a conductivemembrane for interacting with the conductive material 510 to assist inthe transfer of heat. At least a portion of the chamber wall that facesaway from the cylindrical member 110 comprises a thick membrane 611.

Additionally, during generation of the cold slurry using any of theapparatuses and devices described above, the plunger 120 can be used tocreate a negative pressure on the fluid to effect a decrease in thefreezing temperature of the fluid. An example of this is shown in FIGS.11A and 11B. The plunger 120 in 11A is shown prior to being drawnupwards toward the first end 112 of the cold slurry delivery device 100,while the plunger 120 in 11B is being drawn upwards toward the first end112 of the cold slurry delivery device 100 to create negative pressureon the fluid. Accordingly, the pressure on the fluid is lower in 11Bthan it is in 11A.

In accordance with another embodiment of the present invention, coldslurry can be generated in a separate chamber, a slurry generationchamber 300, using a cooling source and an injectable fluid, optionallywith the aid of a solid salt water source. In one aspect, the volume ofthe slurry generation chamber 300 is less than about 1 L, such as lessthan about 800 ml, less than about 700 ml, less than about 600 ml, lessthan about 500 ml, less than about 400 ml, less than about 300 ml, lessthan about 200 ml, less than about 100 ml, less than about 90 ml, lessthan about 80 ml, less than about 70 ml, less than about 60 ml, lessthan about 50 ml, less than about 25 ml, and less than about 10 ml.

The slurry generation chamber 300, as shown in FIG. 12, has a top end312 and a bottom end 314. The top end 312 contains a connector 305. Inone aspect, the slurry generation chamber 300 is divided into at least 3compartments. A first compartment 310 holds an injectable fluid that issuitable for injection into a patient's body. The injectable fluid cancomprise salt, sugar, and/or any other pharmaceutically acceptableexcipient provided above. The first compartment 310 can comprise a rigidhousing or can be flexible, such that a vacuum is formed when fluid isejected from the first compartment 310. In the case that a vacuum isformed, vapor may be created. Accordingly, the slurry generation chamber300 also includes an air space 340 for vapor located towards the top end312 of the chamber 300. In one aspect, a vapor release valve 345 is alsoprovided.

A second compartment 320 can initially be empty or can comprise a solidsalt water source. In one embodiment, the solid salt water source is aplurality of salt water filled particles 340. The particles 340 can beany shape, such as spherical, cylindrical, torus-shaped, conical,square, elliptical, etc. It is to be understood that the particles 340do not have to be perfectly shaped and instead can include imperfectionsand oddities. In one embodiment, the particles 340 are substantiallyspherical. In another embodiment, the particles 340 have nodules orbumps on the outer surface, as shown in FIG. 12. The nodules act toincrease the surface area available for interaction. The nodules alsoprovide additional agitation and ability to separate the particles 340from one another.

The first compartment 310 and the second compartment 320 are separatedfrom one another through a separation member 360. The separation member360 can comprise one or more valves that can be opened upon reaching acertain pressure or upon receipt of a signal from a release triggeroperatively coupled to the separation member 360. Alternatively, theseparation member 360 can comprise a breakable seal that is broken bytwisting a portion of the slurry generation chamber 300 or through theuse of a trigger. Once the separation member 360 has been breached, thefluid from the first compartment 310 and fluid and/or salt water filledparticles 340 contained in the second compartment 320 will mix together.

A third compartment 330 comprises a cooling fluid, the cooling fluidbeing safe for delivery within the patient's body. In a preferredembodiment, the cooling fluid is compressed within the third compartment330. Exemplary cooling fluids include liquid nitrogen, HCF-134A, andother refrigerants which are deemed acceptable for use by theEnvironmental Protection Agency and government entities. Preferably, thecooling fluid is safe for humans.

The third compartment 330 is in fluid communication with the secondcompartment 320 through one or more valves 350. In one embodiment, thevalve 350 is set to open at a predetermined pressure. In anotherembodiment, the valve 350 is opened upon receipt of a signal from arelease trigger 355 that is operatively coupled to the valve 350. In oneaspect, the valve 350 is a one-way valve, such that fluid only flowsthrough the valve 350 in a direction from the third compartment 330 tothe second compartment 320.

Preferably, the contents of the three compartments (310, 320, and 330)are kept separate from each other until just prior to delivery of thecold slurry at the point of care. Keeping the compartments separateensures that the cold slurry is not generated until desired. In thisway, the slurry generation chamber 300 can be manufactured in mass at aseparate facility and shipped without requiring refrigeration; the onlyaction needed to generate a cold slurry at the point of care is theactivation of the release trigger 355 and the shaking of the slurrygeneration chamber 300.

In one particular embodiment, as shown in FIG. 12, in one embodiment,the first compartment 310 is provided toward the top end 312 of theslurry generation chamber 300, the third compartment 330 is providedtoward the bottom end 314 of the slurry generation chamber 300, with themajority of the second compartment 320 located between the firstcompartment 310 and the third compartment 330. In one aspect of theembodiment, a portion of the second compartment 320 surrounds the firstcompartment 310, such that the second compartment 320 is providedbetween the first compartment 310 and the wall of the slurry generationchamber 300.

In operation, the opening of the valve 350 releases cooling fluid fromthe third compartment 330 and into the second compartment 320. Thecooling fluid interacts with the salt water filled particles 340,lowering the temperature of the particles 340 to a desired temperature.The cooling fluid will also lower the temperature of the injectablefluid contained within the first compartment 310 as the cooling fluidflows into the second compartment 320.

Once the salt water filled particles 340 have been chilled to adesirable temperature, intentional breach of the separation member 360occurs, such that the particles 340 and the injectable fluid comingle.The chilled salt water filled particles 340 continue to lower thetemperature of the injectable fluid, such that a cold slurry iseventually formed. The chilled salt water filled particles 340 alsoserve to agitate and separate the ice crystals forming in the coldslurry as the temperature drops. Additionally, the slurry generationchamber 300 is subject to further agitation, such as by shaking theslurry generation chamber 300, with the additional agitation assistingin the cold slurry formation by increasing the interaction between theinjectable fluid and the chilled salt water filled particles 340. Othermeans for agitating the cold slurry can be used, such as vibration androtation, similar to the cold slurry delivery device 100 of FIG. 3.

In one embodiment, once the salt water filled particles 340 have reacheda desirable temperature, the cooling fluid is released from the slurrygeneration chamber 300 prior to breach of the separation member 360.Once the cooling fluid has been released, the separation member 360 isthen breached.

In another embodiment wherein the second compartment 320 is initiallyempty (e.g., particles 340 are not provided to the second compartment320), the release of cooling fluid into the second chamber still occurs.In this embodiment, once released, the cooling fluid will flow into thesecond compartment 320 from the third compartment 330 and will circulatethrough the second compartment 320. The circulation of the cooling fluidin the second compartment will chill the injectable fluid housed withinthe first compartment 310, as was disclosed previously.

After the cold slurry is formed, the cold slurry can be transferred fromthe slurry generation chamber 300 to the cold slurry delivery device100, as shown in FIG. 13. In a preferred embodiment, the cold slurrydelivery device 100 and slurry generation chamber 300 mate through male145 connector and female 305 connector, as shown in FIG. 13A, toremovably couple the slurry generation chamber 300 to the cold slurrydelivery device 100, with the cold slurry being transferred from theslurry generation chamber 300 through the connectors 145, 305. Transfercan be effectuated through either the pulling of the plunger 120 of thecold slurry delivery device 100 to create negative pressure and/or thepushing of a chamber plunger 370. In the embodiment in which the saltwater filed particles 340 are provided to the slurry generation chamber300, a filter (not shown) can be provided just before the cold slurryexits the slurry generation chamber 300 through the female connector305. The filter prevents the salt water filed particles 340 from flowinginto the cold slurry delivery device 100 with the cold slurry and/orfrom clogging the opening of the female connector 305. In oneembodiment, the slurry generation chamber 300 generates enough coldslurry for a single injection using the cold slurry delivery device 100.In another embodiment, the slurry generation chamber 300 generatesenough cold slurry for two or more injections.

Other means for delivering a cold slurry generated in the slurrygeneration chamber 300 are also contemplated. For examples, a catheteror cannula fitted with connective tubing can be coupled to the slurrygeneration chamber 300. In one aspect, a battery powered pump can beprovided with the slurry generation chamber 300 to effectuate the flowof cold slurry through the tubing and into the cannula/catheter fordelivery into a patient's body.

In one aspect of the invention, the fully assembled slurry generationchamber 300 can be provided in a kit along with a device for deliveringcold slurry. In this way, the only required actions to generate anddeliver cold slurry into a patient's body are to activate the slurrygeneration chamber 300 and transfer the cold slurry from the slurrygeneration chamber 300 to the delivery device.

In one aspect of the invention, a temperature sensor is provided tomonitor the temperature of the fluid/cold slurry. Any temperature sensordevice known in the art, such as thermometers, thermocouples, and othertemperature measuring devices can be used in accordance with the presentinvention. Measurements can be taken internal or external to a containerholding the cold slurry. Alternatively or additionally, an additive canbe provided to either or both of the cold slurry or the containerholding the cold slurry that can change color to indicate that a desiredtemperature has been reached and/or that the cold slurry is no longer ata desired temperature.

In another aspect of the invention, the cold slurry generated from theapparatuses and methods described above can be provided to a tissuewithin the body of a patient, for example, for the treatment of apatient. The tissue to which the cold slurry can be administeredincludes one or more of connective, epithelial, neural, joint, cardiac,adipose, hepatic, renal, vascular, cutaneous, and muscle tissue.Additionally methods include delivery of a cold slurry using and/orgenerated by the apparatuses described herein to any one or more of thefollowing locations: proximate to a nerve, proximate to subcutaneousadipose tissue, proximate to breast tissue, proximate to visceral fat,fatty tissue proximate to the pharynx, fatty tissue proximate to thepalate, fatty tissue proximate to the tongue, proximate to a spinal cordlipoma, proximate to visceral fat, proximate to lipomastia, proximate toa tumor, proximate to cardiac tissue, proximate to pericardial fat, andproximate to epicardial fat. Various conditions, disorders or diseaseswhich can be treated through delivery of cold slurry to a subjectinclude obesity, sleep apnea, nerve pain, and any other disease ordisorder such as those disclosed in International ApplicationPublication No. WO/2016/033380, which is incorporated herein in itsentirety. Alternatively or additionally, cold slurry can be delivered toa patient in accordance with the invention to improve the aesthetics ofthe patient through reduction of fat, cellulite, wrinkles, etc., evenwhen the patient is not suffering from a certain condition, disorder ordisease.

In a preferred embodiment, the cold slurry is delivered to or adjacentto adipose tissue (fat tissue) within a patient's body in order toinduce apoptosis of the tissue cells, as shown generally in FIG. 14. Thecold slurry is delivered to the target tissue using a device fordelivery of a cold slurry, such as the cold slurry delivery device 100of FIG. 3 or any other syringe-type device, a catheter or a cannula.

In an exemplary method, an area on a patient's skin through which adevice for delivering cold slurry will enter is cleaned and an entrypoint is marked on the skin. The entry point can be identified,visually, or through the use of one or more imaging technique, such asultrasound, magnetic resonance, and x-ray. The device is then insertedinto the entry point and advanced to the target tissue. The cold slurryis then injected at (or near) the target tissue. An amount of coldslurry can be delivered to multiple sites at (or near) the targettissue. In some instances, injection to multiple sites increases theamount of target tissue that is exposed to the cold slurry and cooled,and can improve the effectiveness of the treatment.

By inducing apoptosis in the tissue cells, fat cells are removed, thusreducing the amount of fat within a patient's body, which in turn canimprove the aesthetics of the patient and/or be used to treat obesity(among other diseases or disorders). Adipose tissue comprises whiteadipose tissue and brown adipose tissue. Adipose tissue can be foundjust beneath the skin (subcutaneous fat), around internal organs(visceral fat), in bone marrow, intermuscular, and within breast tissue.Areas in which the cold slurry can be delivered to fat tissue include,without limitation, the face, neck, submental area under chin, jowls,eyelids, sub orbital fat pockets, posterior neck (buffalo hump), back,shoulders, arms, triceps, biceps, forearms, hands, chest, breasts,abdomen, flanks (love handles), lower back, buttocks (banana roll), hips(saddle bags), anterior and posterior thighs, inner thighs, mons pubis,vulva, knees, above the knees, calves, shin, pretibial area, ankles, andfeet. It is contemplated that the cold slurry can be delivered to anypockets of subcutaneous fat for which reduction of the fat would bedesirable.

EQUIVALENTS

While the present invention has been described in conjunction withcertain preferred embodiments, one of ordinary skill, after reading theforegoing specification, will be able to effect various changes,substitutions of equivalents, and other alterations to the apparatusesand methods set forth herein.

What is claimed is:
 1. An apparatus for production and/or delivery of acold slurry, the apparatus comprising: a cylindrical member comprising:a first end, a second end, and a longitudinal axis extending through thefirst and second ends; an outer surface extending between the first andsecond ends along the longitudinal axis; an interior lumen defined by aninterior wall of the cylindrical member, the interior lumen configuredto receive and hold a cold slurry; a plunger at least partially disposedwithin the interior lumen and configured to move within the cylindricalmember in the direction of the longitudinal axis, and the plungercomprising a head, a plunging member, and a rod extending between thehead and the plunging member along the longitudinal axis of thecylindrical member; at least one needle extending from the second end ofthe cylindrical member; an agitation device coupled to the plungerconfigured to agitate the cold slurry within the interior lumen of thecylindrical member; and a cooling sleeve surrounding at least a portionof the cylindrical member, the cooling sleeve being configured to coolor maintain a temperature of the cold slurry within the interior lumenof the cylindrical member, and including a cap configured to engage withand rotate the plunger of the cylindrical member.
 2. The apparatus ofclaim 1, wherein the agitation device comprises at least one rotationblade extending from the plunging member towards the second end of thecylindrical member; and wherein the agitation device is configured toagitate the cold slurry upon rotation of the plunger.
 3. The apparatusof claim 2, further comprising a motor coupled to the plunger.
 4. Theapparatus of claim 3, wherein the motor is coupled to the rod betweenthe head and the plunging member.
 5. The apparatus of claim 3, whereinthe motor is coupled to the head of the plunger.
 6. The apparatus ofclaim 1, wherein the agitation device comprises a wire extending fromthe plunging member towards the second end of the cylindrical memberalong the longitudinal axis.
 7. The apparatus of claim 6, wherein theagitation device further comprises one or more tentacles extending outfrom the wire and toward the interior wall of the cylindrical member. 8.The apparatus of claim 6, wherein the agitation device further comprisesa motor coupled to the plunger and configured to vibrate the wire. 9.The apparatus of claim 1, wherein the outer surface of the cylindricalmember includes a conductive material.
 10. The apparatus of claim 9,wherein the conductive material is copper.
 11. The apparatus of claim 1,further comprising a sheath surrounding the cylindrical member, thesheath including a conductive material.
 12. The apparatus of claim 11,wherein the conductive material is copper.
 13. The apparatus of claim 1,wherein the cooling sleeve and the cylindrical member are in aconcentric arrangement with a space formed between an inner surface ofthe cooling sleeve and the outer surface of the cylindrical member. 14.The apparatus of claim 13, further comprising at least one tubularmember located within the space, the tubular member disposed axiallyabout and extending at least partially around a circumference of theouter surface of the cylindrical member, and the tubular memberconfigured to contain a cooling fluid.
 15. The apparatus of claim 14,wherein the tubular member is in the shape of a coil.
 16. The apparatusof claim 13, wherein the cap is configured to fit around the first endof the cylindrical member, and to seat with the cooling sleeve towardsthe first end of the cylindrical member; and wherein a seal is providedbetween the cap and the cooling sleeve.
 17. The apparatus of claim 16,wherein a first chemical is provided within an interior space of the capand a second chemical is provided within the space between thecylindrical member and the cooling sleeve, wherein the seal separatesthe first chemical from the second chemical, and wherein an endothermicreaction occurs when the first chemical and the second chemical aremixed together.
 18. The apparatus of claim 17, wherein the firstchemical and second chemical are selected from the group consisting of:water, ammonium chloride, potassium nitrate, sodium thiosulphate,ammonium nitrate, ammonium thiocyanate, and barium hydroxideoctahydrate.
 19. The apparatus of claim 1, further comprising a chamberconfigured to removably couple and supply the cold slurry to theinterior lumen of the cylindrical member.
 20. The apparatus of claim 19,wherein the chamber comprises a top end and a bottom end; wherein thetop end comprising a first connector that mates with a second connectorlocated at the second end of the cylindrical member; and wherein thefirst connector and the second connector are configured to allow thecold slurry to flow from the chamber and into the interior lumen whenmated.
 21. The apparatus of claim 20, wherein the chamber is configuredto produce the cold slurry using a cooling fluid that cools aninjectable fluid.
 22. The apparatus of claim 21, wherein the chambercomprises: a first compartment located at the top end of the chamber andconfigured to contain the injectable fluid; a second compartment locatedbetween the top and bottom ends of the chamber; and a third compartmentlocated at the bottom end of the chamber and configured to contain thecooling fluid.
 23. The apparatus of claim 22, wherein the secondcompartment is configured to contain salt water filled particles. 24.The apparatus of claim 22, wherein the first compartment and the secondcompartment are separated from each other by a separation member. 25.The apparatus of claim 24, wherein the separation member is a breakableseal configured to break, such that a content of the second chambermixes with the injectable fluid in the first compartment.
 26. Theapparatus of claim 24, wherein the second compartment and the thirdcompartment are in fluidic communication with each other through one ormore valves configured to release the cooling fluid in the thirdcompartment into the second compartment when the one or more valves areopened.
 27. An apparatus for delivery of a cold slurry, the apparatuscomprising: a cylindrical member comprising: a first end, a second end,and a longitudinal axis extending through the first and second ends; anouter surface extending between the first and second ends along thelongitudinal axis; an interior lumen defined by an interior wall of thecylindrical member, the interior lumen configured to receive and hold acold slurry; a plunger at least partially disposed within the interiorlumen and configured to move within the cylindrical member in thedirection of the longitudinal axis, and the plunger comprising a head, aplunging member, and a rod extending between the head and the plungingmember along the longitudinal axis of the cylindrical member; at leastone needle extending from the second end of the cylindrical member; anagitation device coupled to the plunger configured to agitate the coldslurry within the interior lumen of the cylindrical member; a coolingsleeve surrounding at least a portion of the cylindrical member, thecooling sleeve being configured to cool or maintain a temperature of thecold slurry within the interior lumen of the cylindrical member, thecooling sleeve and the cylindrical member being arranged concentricallywith a space formed between an inner surface of the cooling sleeve andthe outer surface of the cylindrical member; at least one tubular memberlocated within the space, the tubular member disposed axially about andextending at least partially around a circumference of the outer surfaceof the cylindrical member, and the tubular member configured to containa cooling fluid; and a container surrounding at least a portion of thecooling sleeve and fluidically connected to the tubular member at atleast one location, the container configured to hold a cooling fluid andsupply the cooling fluid to the tubular member.
 28. An apparatus fordelivery of a cold slurry, the apparatus comprising: a cylindricalmember comprising: a first end, a second end, and a longitudinal axisextending through the first and second ends; an outer surface extendingbetween the first and second ends along the longitudinal axis; aninterior lumen defined by an interior wall of the cylindrical member,the interior lumen configured to receive and hold a cold slurry; aplunger at least partially disposed within the interior lumen andconfigured to move within the cylindrical member in the direction of thelongitudinal axis, and the plunger comprising a head, a plunging member,and a rod extending between the head and the plunging member along thelongitudinal axis of the cylindrical member; at least one needleextending from the second end of the cylindrical member; an agitationdevice coupled to the plunger configured to agitate the cold slurrywithin the interior lumen of the cylindrical member; a cooling sleevesurrounding at least a portion of the cylindrical member, the coolingsleeve being configured to cool or maintain a temperature of the coldslurry within the interior lumen of the cylindrical member, the coolingsleeve and the cylindrical member being arranged concentrically with aspace formed between an inner surface of the cooling sleeve and theouter surface of the cylindrical member, the space between thecylindrical member and the cooling sleeve forming a chamber; a containersurrounding at least a portion of the cooling sleeve and fluidicallyconnected to the chamber, the container configured to hold a coolingfluid and supply the cooling fluid to the chamber; and at least oneinlet located between the chamber and the container configured to allowthe cooling fluid to flow from the container and into the chamber. 29.The apparatus of claim 28, further comprising a release mechanismoperably coupled to the at least one inlet to control the flow of thecooling fluid through the inlet.
 30. The apparatus of claim 28, furthercomprising a conductive membrane provided between the chamber and theouter surface of the cylindrical member.
 31. The apparatus of claim 30,wherein the outer surface of the cylindrical member comprises aconductive material; and wherein the conductive membrane and theconductive material are configured to interact with each other when thecylindrical member is received within the cooling sleeve.
 32. Anapparatus for delivery of a cold slurry, the apparatus comprising: acylindrical member comprising: a first end, a second end, and alongitudinal axis extending through the first and second ends; an outersurface extending between the first and second ends along thelongitudinal axis; an interior lumen defined by an interior wall of thecylindrical member, the interior lumen configured to receive and hold acold slurry; a plunger at least partially disposed within the interiorlumen and configured to move within the cylindrical member in thedirection of the longitudinal axis, and the plunger comprising a head, aplunging member, and a rod extending between the head and the plungingmember along the longitudinal axis of the cylindrical member; at leastone needle extending from the second end of the cylindrical member; anagitation device coupled to the plunger configured to agitate the coldslurry within the interior lumen of the cylindrical member; a coolingsleeve surrounding at least a portion of the cylindrical member, thecooling sleeve being configured to cool or maintain a temperature of thecold slurry within the interior lumen of the cylindrical member, thecooling sleeve and the cylindrical member being arranged concentricallywith a space formed between an inner surface of the cooling sleeve andthe outer surface of the cylindrical member; at least one chamberdisposed within the space between the inner surface of the coolingsleeve and the outer surface of the cylindrical member, the at least onechamber extending along a second axis parallel to the longitudinal axisof the cylindrical member, and the at least one chamber configured tocontain a fluid; and a pressurized gas source configured to compress thefluid in the at least one chamber.
 33. The apparatus of claim 32,wherein the at least one chamber includes a second plunger configured tocompress the fluid when activated by the pressurized gas source.
 34. Theapparatus of claim 33, wherein at least a portion of a wall of the atleast one chamber that faces the cylindrical member comprises aconductive membrane.
 35. A method of delivering a cold slurry using adelivery device, the method comprising: providing a fluid to an interiorlumen of a cylindrical member of a delivery device, the cylindricalmember having a plunger; agitating the fluid within the interior lumenusing an agitation device; cooling the fluid within the interior lumento generate cold slurry using a cooling sleeve that at least partiallysurrounds the cylindrical member of the delivery device, the coolingsleeve including a cap engaging with the plunger of the cylindricalmember; and rotating the plunger of the cylindrical member using the capof the cooling sleeve.
 36. The method of claim 35, wherein the agitatingand the cooling of the fluid are performed concurrently.
 37. The methodof claim 35, wherein the agitation device comprises one or more rotationblades coupled to the plunger at least partially disposed within theinterior lumen of the cylindrical member of the delivery device.
 38. Themethod of claim 35, wherein the agitation device comprises a vibrationmechanism.
 39. The method of claim 35, further comprising ejecting thecold slurry from the delivery device using the plunger at leastpartially disposed within the interior lumen of the cylindrical memberof the delivery device.
 40. The method of claim 39, wherein the ejectedcold slurry is delivered to one or more tissue types selected from agroup consisting of: subcutaneous fat, visceral fat, and brown fat. 41.The method of claim 39, wherein the ejected cold slurry is delivered totissue in one or more areas selected from a group consisting of: tissuearound the flank, abdomen, thigh area, upper arm, submental area underthe chin, sub orbital fat pockets, and above the knees.